Human melanoma can develop in a sequence of steps from benign proliferative lesions. Melanocytes isolated and cultured from normal skin and lesions representing each step have been characterized for growth requirements, synthesis of growth factors, and expression of cell surface tumor associated antigens. Still, little is known about the molecular events leading to tumor development and progression towards an aggressive phenotype. Two models have now been established to provide tools for in- depth experimental investigations with a focus on the early stages of melanoma. The first model consists of full-thickness human skin, nevi or primary melanomas of the radial (non-tumorigenic) growth phase that are transplanted to immunodeficient SCID mice and treated in two-step and one- step carcinogenesis protocols for induction of human melanocytic lesions. The protocols involve treatments with the chemical carcinogen DMBA and ultraviolet (UV) light in the UV-B range which are applied alone or in combination. Developing melanocytic lesions will be characterized for expression of growth factors, adhesion receptors, and aberrations in oncogene and suppressor gene expression. The second model aims at 'reconstructing" melanocytic lesions by overexpressing a cell-cell adhesion receptor (MUC18) in melanocytes for induction of "nevi" and two angiogenic growth factors (pleiotrophin and PDGF-B) in biologically early (non- tumorigenic) melanomas for induction of tumorigenic lesions. Overexpression is achieved by gene transfer with adenovirus vectors. To investigate the biological properties of transduced cells, they are incorporated into three-dimensional epidermal and dermal equivalents that resemble normal human skin and that can also be grafted to SCID mice, thus allowing cell-cell contracts between normal and malignant human cells under in vivo experimental conditions. The two experimental models provide excellent tools for a better understanding of the molecular events leading to melanoma development and progression.